Nishida Keigo, Uchida Ryota
Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science.
Yakugaku Zasshi. 2017;137(5):495-501. doi: 10.1248/yakushi.16-00239-1.
Mast cells are hematopoietic-lineage cells that participate in immunoglobulin E (IgE)-associated immune responses, including allergic reactions and parasite resistance. Recent studies have shown that zinc (Zn) ion can behave as an intracellular signaling molecule and that Zn is involved in mast cell activation. We demonstrated that mast cells stimulated through the high-affinity IgE receptor (FcεRI) rapidly release intracellular Zn from the endoplasmic reticulum (ER), and we named this phenomenon the "Zn wave". Furthermore, we found that the L-type calcium channel (LTCC) is the gatekeeper for the Zn wave. LTCC antagonists inhibited the Zn wave, and an agonist was sufficient to induce it. Notably, LTCC was mainly localized to the ER rather than to the plasma membrane in mast cells, and the Zn wave was impaired by LTCC knockdown. We also found that the LTCC-mediated Zn wave positively controlled inflammatory cytokine gene induction by enhancing the DNA-binding activity of nuclear factor-kappa B (NF-κB). These findings indicated that the LTCC has a novel function as a gatekeeper for the Zn wave, which is involved in regulating NF-κB signaling. In this review, we describe our current understanding of Zn signaling, especially with regard to the Zn wave and the role of Zn signaling in mast cells.
肥大细胞是造血谱系细胞，参与免疫球蛋白E（IgE）相关的免疫反应，包括过敏反应和抗寄生虫反应。最近的研究表明，锌（Zn）离子可作为细胞内信号分子，且锌参与肥大细胞的激活。我们证明，通过高亲和力IgE受体（FcεRI）刺激的肥大细胞会迅速从内质网（ER）释放细胞内锌，我们将这种现象命名为“锌波”。此外，我们发现L型钙通道（LTCC）是锌波的守门者。LTCC拮抗剂可抑制锌波，而一种激动剂就足以诱导锌波。值得注意的是，LTCC主要定位于肥大细胞的内质网而非质膜，并且LTCC敲低会损害锌波。我们还发现，LTCC介导的锌波通过增强核因子-κB（NF-κB）的DNA结合活性来正向控制炎性细胞因子基因的诱导。这些发现表明，LTCC作为锌波的守门者具有新功能，其参与调节NF-κB信号传导。在本综述中，我们描述了我们目前对锌信号传导的理解，特别是关于锌波以及锌信号传导在肥大细胞中的作用。
